Radiopharmaceutics

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Radiopharmaceutics
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What is Radiopharmacy?

• Radiopharmacy Nuclear Pharmacy
• Nuclear pharmacy is a specialty area of pharmacy
  practice dedicated to the compounding and
  dispensing of radioactive materials for use in
  nuclear medicine procedures.

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Introduction

• All substances are made of atoms.
• These have electrons (e) around the outside
  (negatively charged),
• and a nucleus in the middle.
• The nucleus consists of protons (positively
  charged) and neutrons (neutral).
• The atomic number of an atom is the number of
  protons in its nucleus.
• The atomic mass is the number of protons
  neutrons in its nucleus.

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Introduction

• Isotopes of an atom have the same number of
  protons, but a different number of neutrons.
• Example
• Consider a carbon atom It has 6 protons and 6
  neutrons - we call it "carbon-12" because it has
  an atomic mass of 12 (6 plus 6).
• One useful isotope of carbon is "carbon-14",
  which has 6 protons and 8 neutrons.
• Radioisotopes, Radionuclides unstable isotopes
  which are distinguishable by radioactive
  transformation.
• Radioactivity the process in which an unstable
  isotope undergoes changes until a stable state is
  reached and in the transformation emits energy in
  the form of radiation (alpha particles, beta
  particles and gamma rays).

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Introduction

• Radiation refers to particles or waves coming
  from the nucleus of the atom (radioisotope or
  radionuclide) through which the atom attempts to
  attain a more stable configuration.

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Types of radioactivityHow to produce a
radioactive nuclide ?

• 1- Natural radioactivity
• Nuclear reactions occur spontaneously
• 2- Artificial radioactivity
• The property of radioactivity produced by
  particle bombardment or electromagnetic
  irradiation.
• A- Charged-particle reactions
• e.g. protons (1 1H)
• e.g. deuterons (2 1H)
• e.g. alpha particles (4He)

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Types of radioactivity

• B- Photon-induced reactions
• The source of electromagnetic energy may be
  gamma-emitting radionuclide or high-voltage x-ray
  generator.
• C- Neutron-induced reactions
• It is the most widely used method
• It is the bombardment of a nonradioactive target
  nucleus with a source of thermal neutrons.

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Production of radionuclides

• 1- Charged particle bombardment
• Radionuclides may be produced by bombarding
  target materials with charged particles in
  particle accelarators such as cyclotrons.
• A cyclotron consists of
• Two flat hollow objects called dees.
• The dees are part of an electrical circuit.
• On the other side of the dees are large magnets
  that (drive) steer the injected charged particles
  (protons, deutrons, alpha and helium) in a
  circular path
• The charged particle follows a circular path
  until the particle has sufficient energy that it
  passes out of the field and interact with the
  target nucleus.

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Cyclotron
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Production of radionuclides

• 2- Neutron bombardment
• Radionuclides may be produced by bombarding
  target materials with neutrons in nuclear
  reactors
• The majority of radiopharmaceuticals are produced
  by this process

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Production of radionuclides

• 3- Radionuclide generator systems
• Principle
• A long-lived parent radionuclide is allowed to
  decay to its short-lived daughter radionuclide
  and the latter is chemically separated in a
  physiological solution.
• Example
• technetium-99m, obtained from a generator
  constructed of molybdenum-99 absorbed to an
  alumina column.

Eluted from the column with normal saline
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99Mo/99mTc Generator

• Parent 99Mo as molybdate
• Half-life 66 hr.
• Decays by - emission, gamma 740, 780 keV.
• High affinity to alumina compared to
  .
• Daughter as pertechnetate
• Adsorbent Material Alumina (aluminum oxide,
  )
• Eluent saline (0.9 NaCl)
• Eluate

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Radioactive decay

• The rate of decay can be described by
• N No e-?t
• where N is the number of atoms at elapsed time t,
  No is the number of atoms when t 0, and ? is
  the disintegration constant characteristic of
  each individual radionuclide.
• T½ 0.693 / ?
• The intensity of radiation can be described by
• I I0 e - 0.693/ T1/2

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Radioactive Decay Law
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Radioactive decay

• Half life  symbol t1/2  the time taken for the
  activity of a given amount of a radioactive
  substance to decay to half of its initial value.
• Total activity  symbol A  number of decays an
  object undergoes per second.
• Radionuclidic purity- is that percentage of the
  total radioactivity that is present in the form
  of the stated radionuclide.

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Mode of radioactive decay

• Radioactive decay is the process in which an
  unstable atomic nucleus spontaneously loses
  energy by emitting ionizing particles and
  radiation.
• This decay, or loss of energy, results in an atom
  of one type, called the parent nuclide
  transforming to an atom of a different type,
  named the daughter nuclide.
• When an unstable nucleus decays, It may give out-

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1- Alpha particle decay

• Alpha particles are made of 2 protons and 2
  neutrons.
• We can write them as , or ,
  because they're the same as a helium nucleus.
• This means that when a nucleus emits an alpha
  particle, its atomic number decreases by 2 and
  its atomic mass decreases by 4.
• Alpha particles are relatively slow and heavy.
• They have a low penetrating power - you can stop
  them with just a sheet of paper.
• Because they have a large charge, alpha particles
  ionise other atoms strongly.
• Alpha-decay occurs in very heavy elements, for
  example, Uranium and Radium.

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Since alpha particles cannot penetrate the dead
layer of the skin, they do not present a hazard
from  exposure external to the body. However,
due to the very large number of ionizations they
produce in a very short distance, alpha emitters
can present a serious hazard when they are in
close proximity to cells and tissues such as the
lung. Special precautions are taken to ensure
that alpha emitters are not inhaled, ingested or
injected.
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2- Beta particle decay

• Beta particles have a charge of minus 1. This
  means that beta particles are the same as an
  electron. We can write them as or ,
  because they're the same as an electron.
• This means that when a nucleus emits a
  -particle the atomic mass is unchanged
• the atomic number increases or
  decreases by 1.
• They are fast, and light.
• Beta particles have a medium penetrating power -
  they are stopped by a sheet of aluminium.
• Example of radiopharmaceutical emits ,
  phosphorus-32
• Beta particles ionise atoms that they pass, but
  not as strongly as alpha particles do.

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Beta particles are much less massive and less
charged than alpha particles and interact less
intensely with atoms in the materials they pass
through, which gives them a longer range than
alpha particles.
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3- Gamma ray

• Gamma rays are waves, not particles. This means
  that they have no mass and no charge.
• in Gamma decay
• atomic number unchanged
• atomic mass unchanged.
• Gamma rays have a high penetrating power - it
  takes a thick sheet of metal such as lead to
  reduce them.
• Gamma rays do not directly ionise other atoms,
  although they may cause atoms to emit other
  particles which will then cause ionisation.
• We don't find pure gamma sources - gamma rays are
  emitted alongside alpha or beta particles.

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3- Gamma ray

• Useful gamma sources inculde Technetium-99m,
  which is used as a "tracer" in medicine.
• This is a combined beta and gamma source, and is
  chosen because betas are less harmful to the
  patient than alphas (less ionisation) and because
  Technetium has a short half-life (just over 6
  hours), so it decays away quickly and reduces the
  dose to the patient.

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Alpha particles are easy to stop, gamma rays are
hard to stop.
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Mode of radioactive decay
Type of Radiation Alpha particle Beta particle Gamma ray
Symbol or
Charge 2 -1 0
Speed slow fast Very fast
Ionising ability high medium 0
Penetrating power low medium high
Stopped by paper aluminium lead
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Radiation measurement

• ( R) the roentgen for exposure
• Is the amount of ? radiation that produces
  ionization of one electrostatic unit of either
  positive or negative charge per cubic centimeter
  of air at 0 ºC and 760 mmHg.
• (rad) radiation absorbed dose is a more universal
  unit, it is a measure of the energy deposited in
  unit mass of any material by any type of
  radiation.
• (rem) has been developed to account for the
  differences in effectiveness of different
  radiations in causing biological damage.
• Rem rad ? RBE
• RBE is the relative biological effectiveness of
  the radiation.

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Radiation measurement

• The basic unit for quantifying radioactivity
  (i.e. describes the rate at which the nuclei
  decay).
• Curie (Ci)
• Curie (Ci), named for the famed scientist Marie
  Curie
• Curie 3.7 x 1010 atoms disintegrate per
  second (dps)
• Millicurie (mCi) 3.7 x 107 dps
• Microcurie (uCi) 3.7 x 104 dps
• Becquerel (Bq)
• A unit of radioactivity. One becquerel is equal
  to 1 disintegration per second.

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Properties of an Ideal DiagnosticRadioisotope

• Types of Emission
• Pure Gamma Emitter (Alpha Beta Particles are
  unimageable Deliver High Radiation Dose.)
• Energy of Gamma Rays
• Ideal 100-250 keV e.g.
• Suboptimallt100 keV e.g.
• gt250 keV e.g.
• Photon Abundance
• Should be high to minimize imaging time

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Properties of an Ideal DiagnosticRadioisotope

• Easy Availability
• Readily Available, Easily Produced
  Inexpensive
• e.g.
• Target to Non target Ratio
• It should be high to
• maximize the efficacy of diagnosis
• minimize the radiation dose to the patient
• Effective Half-life
• It should be short enough to minimize the
  radiation dose to patients and long enough to
  perform the procedure. Ideally 1.5 times the
  duration of the diagnostic procedure.

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Properties of an Ideal DiagnosticRadioisotope

• Example For a Bone Scan which is a 4-h
  procedure, 99mTc- phosphate compounds with an
  effective half-life of 6 h are the ideal
  radiopharmaceuticals
• Patient Safety
• Should exhibit no toxicity to the patient.
• Preparation and Quality Control
• Should be simple with little manipulation.
• No complicated equipment
• No time consuming steps

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Preparation of Radiopharmaceutical

• 1- Sterilization
• - Radiopharmaceutical preparations intended for
  parenteral administration are sterilized by a
  suitable method.
• Terminal sterilization by autoclaving is
  recommended for heat stable products
• For heat labile products, the filteration method
  is recommended.
• 2- Addition of antimicrobial preservatives
• Radiopharmaceutical injections are commonly
  supplied in multidose containers.

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Preparation of Radiopharmaceutical

• The requirement of the general monograph for
  parenteral preparations that such injections
  should contain a suitable antimicrobial
  preservative in a suitable concentration does not
  necessarily apply to radiopharmaceutical
  preparations.
• A reason for this exemption is that many common
  antimicrobial preservatives (for example, benzyl
  alcohol) are gradually decomposed by the effect
  of radiation in aqueous solutions.

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3- Compounding

• compounding can be as simple as
• - adding a radioactive liquid to a commercially
  available reagent kit
• as complex as
• 1- the creation of a multi-component reagent kit
• N.B. Kit for radiopharmaceutical preparation
• means a sterile and pyrogen-free reaction vial
  containing the nonradioactive chemicals e.g.,
  complexing agent (ligand), reducing agent,
  stabilizer, or dispersing agent that are
  required to produce a specific radiopharmaceutical
  after reaction with a radioactive component.
• 2- the synthesis of a radiolabeled compound via a
  multi-step preparation process.

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3- Compounding

• The process of compounding radiopharmaceuticals
  must be under the supervision of recognized
  nuclear physician or a radiopharmacist.
• STABILITY OF COMPOUNDED PREPARATIONS
• All extemporaneously compounded parenteral
  radiopharmaceutical preparations should be used
  no more than 24 hours post compounding process
  unless data are available to support longer
  storage.

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Radiation shielding

• Adequate shielding must be used to protect
  laboratory personnel from ionizing radiation.

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Pro-Tec II Syringe Shield
Guard Lock PET Syringe Shield
Pro-Tec V Syringe Shield
Color Coded Vial Shields
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Vial Shield
Unit Dose Pig
High Density Lead Glass Vial Shield
Sharps Container Shields
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Radiation shielding

• Alpha and beta radiations are readily shielded
  because of their limited range of penetration.
• The alpha particles are mono-energetic and have a
  range of a few centimetres in air.
• aluminium, glass, or transparent plastic
  materials, are used to shield sources of beta
  radiation.
• Gamma radiation is commonly shielded with lead
  and tungsten.

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Radiopharmaceutical quality control

• Visual Inspection of Product
• Visual inspection of the compounded
  radiopharmaceutical shall be conducted to ensure
  the absence of foreign matter and also to
  establish product identity by confirming that
• a liquid product is a solution, a colloid, or a
  suspension
• a solid product has defined properties that
  identify it.
• Assessment of Radioactivity
• -The amount of radioactivity in each compounded
  radiopharmaceutical should be verified and
  documented prior to dispensing, using a proper
  standardized radionuclide (dose) calibrator.

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Radiopharmaceutical quality control

• Radionuclidic Purity
• - Radionuclidic purity can be determined with the
  use of a suitable counting device
• -The gamma-ray spectrum, should not be
  significantly different from that of a
  standardized solution of the radionuclide.
• Radiochemical purity
• Radiochemical purity is assessed by a variety of
  analytical techniques such as
• liquid chromatography - paper
  chromatography
• - thin-layer chromatography -
  electrophoresis
• the distribution of radioactivity on the
  chromatogram is
• determined.

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Radiopharmaceutical quality control

• Verification of Macroaggregate Particle Size and
  Number
• pH
• Microbiological Control (sterility test) and
  Bacterial Endotoxin Testing

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Radiopharmaceutical quality control

• Labelling
• The label on the outer package should include
• a statement that the product is radioactive or
  the international symbol for radioactivity
• the name of the radiopharmaceutical preparation
• the preparation is for diagnostic or for
  therapeutic use
• the route of administration
• the total radioactivity present (for example, in
  MBq per ml of the solution)
• the expiry date
• the batch (lot) number
• for solutions, the total volume
• any special storage requirements with respect to
  temperature and light
• the name and concentration of any added microbial
  preservative

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Application of radiopharmaceuticals

• 1- Treatment of disease
• (therapeutic radiopharmaceuticals)
• They are radiolabeled molecules designed to
  deliver therapeutic doses of ionizing radiation
  to specific diseased sites.
• Chromic phosphate P32 for lung, ovarian,
  uterine, and prostate cancers
• Sodium iodide I 131 for thyroid cancer
• Samarium Sm 153 for cancerous bone tissue
• Sodium phosphate P 32 for cancerous bone tissue
  and other types of cancers
• Strontium chloride Sr 89 for cancerous bone tissue

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Application of radiopharmaceuticals

• 2- As an aid in the diagnosis of disease
  (diagnostic radiopharmaceuticals)
• The radiopharmaceutical accumulated in an organ
  of interest emit gamma radiation which are used
  for imaging of the organs with the help of an
  external imaging device called gamma camera.
• - Radiopharmaceuticals used in tracer techniques
  for measuring physiological parameters (e.g. 51
  Cr-EDTA for measuring glomerular filtration
  rate).
• Radiopharmaceuticals for diagnostic imaging
• (e.g.99m TC-methylene diphosphonate (MDP) used in
  bone scanning).